27 April 2011

[A] quick, inexpensive, and easy to administer physiological measure, pupil dilation in response to emotional words, not only reflects activity in brain regions involved in depression and treatment response but can predict which patients are likely to respond to cognitive therapy[.]. . . activity in the brain's cortical emotion regulatory systems is strongly related to pupil size when people are viewing emotion-laden words . . . It is because of this relationship between eye and brain that pupil measurements predict the response to cognitive therapy."

Cognitive therapy is a type of psychotherapy designed to help individuals overcome difficulties by modifying negative or irrational thoughts and behavior, which, in turn, can improve mood and reduce stress. It is usually completed in weekly sessions, with 10-20 sessions being effective for most individuals who benefit.

Although up to 60% of people with major depressive disorder respond to cognitive therapy (CT) in controlled trials, clinicians do not routinely use standardized assessments to inform which patients should receive this treatment. Inexpensive, noninvasive prognostic indicators could aid in matching patients with appropriate treatments. Pupillary response to emotional information is an excellent candidate, reflecting limbic reactivity and executive control. This study examined 1) whether pretreatment assessment of pupillary responses to negative information were associated with remission in CT and 2) their associated brain mechanisms.

We examined whether pretreatment pupillary responses to emotional stimuli were prognostic for remission in an inception cohort of 32 unipolar depressed adults to 16 to 20 sessions of CT. Twenty patients were then assessed on the same task using functional magnetic resonance imaging. Pupillary responses were assessed in 51 never-depressed controls for reference.

Remission was associated with either low initial severity or the combination of higher initial severity and low sustained pupillary responses to negative words (87% correct classification of remitters and nonremitters, 93% sensitivity, 80% specificity; 88% correct classification of high-severity participants, p &lt; .01, 90% sensitivity, 92% specificity). Increased pupillary responses were associated with increased activity in dorsolateral prefrontal regions associated with executive control and emotion regulation. For patients with higher severity, disruptions of executive control mechanisms responsible for initiating emotion regulation, which are indexed by low sustained pupil responses and targeted in therapy, may be key to remitting in this intervention. These mechanisms can be measured using inexpensive noninvasive psychophysiological assessments.

The small study obviously needs to be replicated in a larger sample before being used on a widespread basis, but the 88% rate at which this simple test determines if high severity depressed patients will respond to cognitive therapy, compared to a 60% response rate in the absence of screening, is a major improvement for a technique that requires no investment in drugs or equipment and only minimal additional training for mental health practitioners. This test could spare more than half of severely clinically depressed individuals time and misery trying cognitive therapy that is unlikely to be effective for them, allowing them to use alternative therapies like drug treatments that are likely to be more effective for them immediately, while allowing about half of severely clinically depressed individuals to receive cognitive therapy, knowing that it has a very high probability of being successful, and avoiding the need for them to undergo a psychiatric drug treatment regime that is unnecessary for their recovery. The fact that the benefit is statistically significant at the 99% level in this small study also makes a study calculated to replicate this result look like a promising good investment.

Given that clinical unipolar depression is one of the most common mental health conditions, and is by far the most common one that is not typically congenital, which makes it disproportionately likely to be a condition dealt with by a primary care physician as opposed to a specialist mental health care professional, this kind of advance has particularly great practical relevance. Also, since unipolar depression is so common, the cost savings to the health care system of a diagnostic tool for determining what kind of treatment will be most effective could be an evidence based medicine technique that could make a material dent in the overall cost of mental health care.

Since this is a diagnostic approach, rather than a drug or device, it also doesn't need a long and costly approval process from the Food and Drug Administration. Funding of a simple large scale replication of this study which could be completed in a year or two, would be enough to include this diagnostic technique as part of the standard by the book treatment regime for unipolar depression nationally. Of course, since this isn't an approach would have a biotech company backing it, this kind of study almost necessarily would need to be funded by the public sector, for example, through a National Institute of Mental Health (NIHM) grant.

The real value of treatment effectiveness prediction tools as a means to improve the quality of patient care while reducing health care costs, a field which is coming into its own as a subfield of psychiatry and psychology, also suggests another funding possibility. Health insurance companies have historically viewed themselves primarily as financial institutions and as institutions through which patients can collectively bargain for provider health care pricing. But, the health insurance industry might be well advised to develop and fund a non-profit research foundation to develop treatment effectiveness prediction tools that do not have drug companies or medical equipment makers to fund them, as a way to promote health enhancing quality control.

The benefits of this little study aren't just practical in an immediate sense either. This is some of the hardest empirical evidence yet that there are medically relevant subtypes of unipolar depression in existence, with some indication of what the underlying neurological basis of that subtyping might involve. One of the deep issues in psychiatric classification of mental health conditions, for which the DSM-IV is the current industry standard, is that diagnosis of psychiatric conditions is almost entirely based upon non-physiological symptoms. It is entirely possible that some common DSM-IV conditions are really a cluster of separate conditions with similar symptoms but different causes (and hence different courses of treatment that are likely to be effective), and that other common DSM-IV conditions currently viewed are in fact merely distinctive syndromes that arrives when separate co-morbid conditions are present.

For example, this study shows that there are at least two types of unipolar depression, one of which is talk therapy responsive and one of which is not. This very likely indicates that the causes of the two types of unipolar depression are different. If this insight in incorporated into prior research on the causes of unipolar depression, the sometimes muddy and contradictory theories about what causes unipolar depression and how it can best be addressed might be clarified. One leading theory regarding the cause of unipolar depression conceptualizes it as a situation where prolonged stress and anxiety cause the body's normal responses to stress to shut down and try the new strategy of becoming depressed to deal with the situation. This might be a primary causal mechanism in one but not the other of subtypes of unipolar depression. If so, somewhat muddy data linking this cause to depression might become much more definitive with regard to the relevant subtype of depression, while clearing the decks for a search for one or more alternative causal mechanisms for the other subtype of depression.

Another possibility is that the pupil dilation response to emotion laden words may be a congenital element of a person's personality that is present even in the absence of unipolar depression. If this is the case, this trait might be one of many that is routinely tested for in children or young adults along with traits like blood type. Children with the trait might be at higher risk for the cognitive therapy responsive subtype of depression. Similarly, medical records could indicate which children are at risk for non-responsiveness to cognitive therapy as a treatment for unipolar depression. Since the physiological test for this trait is quite objective and easy to administer on a mass basis, it might also be possible to see if this trait corrolates with other mental health conditions, particularly those which are often co-morbid with unipolar depression (a co-mordidity pattern that might be more stark when restricted to a particularly subtype of depression), and to determine if it has a hereditary component. Patterns of co-morbidities associated with a particular subtype of unipolar depression might shed insight into the causal mechanism of a variety of mental health conditions which in turn might shed light on the kind of treatment regimes that are likely to be effective for those co-morbid mental health conditions.

Indeed, it might even be possible to provide these children or young adults, on a prophylactic basis, the kind of cognitive training that people with unipolar depression receive after they are diagnosed to help these individuals deal with situations that could lead to clinical depression before they happen.

There is no obvious reason that the benefits of cognitive behavioral therapy, which boils down to teaching people habits of thinking and mental tools for coping with certain kinds of problematic cognitive habits or tendencies, in general, can't be almost as effective when administered in advance as they are when administered as therapy after the fact. It might be possible to put together a set of empirically validated cognitive behavioral therapy regimes into a comprehensive set of coping skills that could be transmitted on a mass basis in a manner not unlike the model by which we instruct people in first aid, CPR, rescue breathing, the use of abdominal thrusts to respond to choking incidents, the proper way to respond to house fires, tornados and tsunamis, or suicide and bullying prevention programs. People who experience cognitive behavioral therapy responsive conditions anyway may benefit for refresher instruction and may be able to make more sense of what these therapies involve when they actually have the conditions that they are designed to alleviate, but it isn't unreasonable to think that this kind of public health preparedness model could materially reduce the overall incidence and impact of many common mental health conditions, some of which are subclinical or would otherwise never be diagnosed as such.